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Aminoboranes As New Iminium Ion Generators in Amination Reactions*

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Aminoboranes As New Iminium Ion Generators in Amination Reactions* Pure Appl. Chem., Vol. 78, No. 7, pp. 1377–1387, 2006. doi:10.1351/pac200678071377 © 2006 IUPAC Aminoboranes as new iminium ion generators in amination reactions* Michinori Suginome Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan Abstract: The utilization of aminoborane derivatives in amination reactions such as Strecker- type aminative cyanation, Mannich-type reaction, and reductive amination is described. Bis(dialkylamino)cyanoboranes and bis(dialkylamino)boron enolates underwent the concur- rent transfer of the amino group and either the cyano or the enoxy group from the boron to carbonyl carbon atom in their reaction with aldehydes, leading to the formation of α-amino nitriles and β-amino ketones, respectively. Bis(dialkylamino)borane derivatives that lack the additional nucleophilic groups on the boron atoms were found to serve as effective genera- tors of iminium ions from aldehydes. In the presence of these aminoboranes, reactions of aldehydes with ketene silyl acetals or silyl enol ethers take place, giving Mannich-type prod- ucts, i.e., β-amino esters and ketones, selectively. Using diisopropylamino-substituted boron compounds, which are designed as “universal” iminium ion generators, reactions of free sec-amines, aldehydes, and ketene silyl acetals proceed efficiently, giving β-amino esters in which the amino groups are derived exclusively from the free amines. The use of the univer- sal iminium ion generator is also effective for reductive amination of aldehydes, in which NaBH4 is used as a hydride donor. Keywords: organic synthesis; boron; α-amino nitriles; β-amino esters; β-amino ketones. INTRODUCTION Organoboron compounds play a key role in synthetic organic chemistry, as essential agents in the effi- cient and selective execution of a variety of fascinating transformations [1]. In particular, remarkable progress has been made in the transition-metal-catalyzed synthesis and reactions of organoboron com- pounds. Further developments of boron-based reactions are highly important for the efficient synthesis of organic molecules. We have been involved in the development of new boron reagents for organic synthesis. Our focus has been on the interesting reactivities of silylboranes [2–7] and cyanoboranes [8–10], which are now recognized as versatile boron reagents in organic synthesis. In the course of our study on cyanoboranes, we became aware of the interesting function of amino groups bound to the boron atom. The function of the amino-substituted boron compounds could be attributed to “efficient iminium ion generation” from carbonyl derivatives, which is generally accepted as the key step in a wide variety of amination reac- tions such as Strecker-type aminative cyanation [11], Mannich reaction [12,13], and reductive amina- tion [14,15]. *Paper based on a presentation at the 12th International Meeting on Boron Chemistry (IMEBORON-XII), Sendai, Japan, 11–15 September 2005. Other presentations are published in this issue, pp. 1299–1453. 1377 1378 M. SUGINOME Aminoboranes have been utilized as important synthetic intermediates in the synthesis of organoboron compounds [16]. The major role of the amino groups on the boron atoms is to protect the boron compounds from excessive substitution by strong nucleophiles, such as alkoxide and organometallic reagents. The additional and important feature of the amino groups is the easiness of de- protection, which is achieved just by treating them with alcohols. However, in spite of the frequent use of aminoboranes in the synthesis of organoboron compounds, they found no particular applications in synthetic organic chemistry. Herein, we describe a new synthetic function of aminoborane derivatives for efficient iminium ion generation from carbonyl compounds. We demonstrate Strecker-type amina- tive cyanation [8], Mannich reaction [17,18], and reductive amination reaction [19] with the use of aminoborane as new iminium ion generators. AMINATIVE CYANATION (STRECKER-TYPE REACTION) WITH BIS(DIALKYLAMINO)CYANOBORANES Our recent reports have shown that cyanoboranes bearing amino groups on the boron atom undergo transition-metal-catalyzed additions to carbon–carbon triple bonds [9,10]. In the course of the research project, we examined reactions of bis(dialkylamino)cyanoboranes with carbonyl compounds. Initial ex- periment was carried out for benzaldehyde in tetrahydrofuran (THF)with the use of an equimolar amount of bis(diethylamino)cyanoborane at room temperature, resulting in the formation of a cyanation product in high yield (eq. 1). The cyanation product was identified as α-amino nitrile 3a, in which not only the cyano group, but also the diethylamino group was introduced nucleophilically to the carbonyl carbon atom. The finding on the highly efficient, concurrent transfer of the amino and the cyano groups prompted us to examine the generality of the reaction. (1) Under the same reaction conditions, a series of aldehydes including p-substituted aromatic, heteroaromatic, α,β-unsaturated, and aliphatic aldehydes were reacted with a molar equivalent of bis(diethylamino)cyanoborane, giving the corresponding α-diethylamino nitriles in high yields (Table 1, entries 1–9). Moreover, amino nitriles having other amino groups were obtained by using boron cyanides bearing the corresponding amino groups (entries 10–14). © 2006 IUPAC, Pure and Applied Chemistry 78, 1377–1387 Aminoboranes as new iminium ion generators 1379 Table 1 Reaction of bis(dialkylamino)cyanoboranes with carbonyl compoundsa. 1 2 b Entry R , R 1 (NR2)Temp/°C Time/h % Yield (aldehyde or ketone) 1 2 1 2b (R = p-MeOC6H4, R = H) 1a (NEt2)r.t. 8 93 1 2 2 2c (R = p-NO2C6H4, R = H) 1a r.t. 11 92 3 2d (R1 = 2-furyl, R2 = H) 1a r.t. 20 94 4 2e (R1 = 2-pyridyl, R2 = H) 1a r.t. 23 99 5 2f (R1 = (E)-PhCH=CH, R2 = H) 1a r.t. 6 95 6 2g (R1 = n-Hexyl, R2 = H) 1a r.t. 1 96 1 2 7 2h (R = PhCH2CH2, R = H) 1a r.t. 1 94 8 2i (R1 = c-Hexyl, R2 = H) 1a r.t. 7 98 9 2j (R1 = t-Bu, R2 = H) 1a r.t. 14 97 10 2i 1b (NBn2)r.t. 4 92 11 2i 1c (pyrrolidino)r.t. 1 99 12 2i 1d (morpholino)r.t. 2 99 c i 13 2i 1e (NPr 2)50 °C 30 92 14c 2a (R1 = Ph, R2 = H) 1e 50 °C 150 99 15 2k (R1 = Me, R2 = Me) 1d r.t. 20 99 1 2 16 2l (R = PhCH2CH2, R = Me) 1d 50 °C 24 99 17 2m (R1 = Ph, R2 = Me) 1d 50 °C 24 92 1 2 18 2n (R , R = –(CH2)5–) 1d r.t. 5 96 1 2 19 2o (R , R = –(CH2)4–) 1d r.t. 5 92 a1 (0.40 mmol) and aldehyde or ketone (0.40 mmol) were reacted in THF (0.7 mL) at room temperature unless otherwise noted. bIsolated yield. c1.1 equiv of 1e was used. The reaction could also be applied to ketones (entries 15–19). Cyclohexanone, cyclopentanone, and acetone underwent the aminative cyanation at room temperature in high yields. Higher temperature (50 °C) was needed to obtain the α-amino nitrile products in high yields in the reaction of acetophenone and 4-phenylbutan-2-one (entries 16 and 17). We presume the reaction mechanism as follows (Scheme 1). Nucleophilic attack of the amino group on the boron atom to the carbonyl carbon atom is followed by four-membered ring formation. Cleavage of the B–N and C–O bonds in the four-membered ring intermediate generates an iminium ion 4 with a boron-containing counter anion. The boron-bound nucleophilic group attacks the iminium ion, leading to the formation of the α-amino nitrile. Scheme 1 Possible mechanism for the aminative nucleophilic reaction using bis(dialkylamino)boranes having a nucleophilic group on the boron atom. © 2006 IUPAC, Pure and Applied Chemistry 78, 1377–1387 1380 M. SUGINOME MANNICH-TYPE REACTION USING BIS(DIALKYLAMINO)BORON ENOLATES On the basis of the presumed reaction mechanism, we examined the reactivity of aminoborane deriva- tives that carry other nucleophilic group on the boron atom (Nu in Scheme 1). We were particularly in- terested in the reactivity of bis(dialkylamino)boron enolates, which carries nucleophilic enoxy group on the boron atom in place of the cyano group in the bis(dialkylamino)boron cyanides. The bis(dialkylamino)boron enolates were prepared via the generation of the corresponding lithium enolate and subsequent reaction with bis(dialkylamino)boron chloride. For instance, bis(di- ethylamino)boron enolate 5a of acetophenone was isolated by distillation in 89 % yield. The aminoboron enolate 5a was then subjected to the reaction with benzaldehyde at 50 °C in THF. Within 5 h, β-amino ketone 6a, a Mannich product, was formed in 84 % yield with no formation of the corre- sponding aldol product (eq. 2). (2) Mannich-type products were also obtained in the reactions of the aminoboron enolates 5a with substituted benzaldehydes, paraformaldehyde, and polymeric glyoxylic acid ethyl ester (Table 2, entries 1–4 and 9). The generality of the new Mannich-type reaction was further examined by using several aminoboranes having different amino and enoxy groups (entries 5–10). A series of benzaldehyde-de- rived boron enolates having diallylamino and pyrrolidino groups afforded the corresponding β-amino ketones in high yields (entries 5 and 6). In these reactions, use of dimethylformamide (DMF) as a sol- vent resulted in acceleration of the reaction rate. The boron enolate having a disubstituted β-carbon atom gave the corresponding product, although a little higher temperature was needed (entry 7). In this reaction, it was found to be essential to use DMF as a solvent. The acetone-derived diaminoboron eno- late successfully gave the corresponding Mannich-type product in high yield (entry 8). Table 2 Reaction of bis(dialkylamino)boron enolates with carbonyl compoundsa. Entry Enolate 52(R3)Temp/°C Solvent Product 1 2 b (R , R , NR2)(% yield) 1 5a (Ph, H, NEt2) 2a (Ph)50 THF 6a (84) 2 5a 2b (p-MeOC6H4)50 THF 6b (87) 3 5a 2p (p-NCC6H4)50 THF 6c (97) 4 5a 2q (H)50 DMF 6d (90) 5 5b (Ph, H, N(allyl)2) 2a 50 THF 6e (88) 6 5c (Ph, H, pyrrolidino) 2a 50 THF 6f (66) 7 5d (Ph, Me, NEt2) 2a 80 DMF 6g (63) 8 5e (Me, H, NEt2) 2a 50 THF 6h (84) 9 5a 2r (CO2Et)50 DMF 6i (86) 10 5d 2r 50 DMF 6j (83) a5 (0.25 mmol) and aldehyde (0.50 mmol) were reacted in THF (0.5 mL) or DMF (0.5 mL) at the indicated temperatures.
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